Expression of Wnt3a in hepatocellular carcinoma and its effects on cell cycle and metastasis

Abstract

Invasion and metastasis are the primary causes of mortality from hepatocellular carcinoma (HCC). Effective inhibition against participants in the tumourigenesis and metastasis process is critical for treatment of HCC. Wnt3a is involved in the development and metastasis of many malignant tumours. However, the specific mechanisms of Wnt3a-mediated cell proliferation, invasion and metastasis in HCC remain unclear. In this study, we found that Wnt3a and its target gene c.Myc showed higher expression in tumour tissues than normal liver tissues in HCC patients; 71.8% of the cases studied had high Wnt3a and c.Myc expression levels (n=32); Wnt3a expression positively correlated with its target genes MMP.7 and c.Myc. Intriguingly, the expression of Wnt3a, MMP.7 and c.Myc is significantly correlated with Notch3 and Hes1 expression. In vitro experiments showed that Wnt3a was highly expressed in MHcc97H and SK.Hep.1 cells. Therefore, Wnt3a expression was silenced with siRNA, and then, MTT, flow cytometry, wound healing and Transwell assays were performed to analyse cell proliferation, cycle, migration and invasion. The results demonstrated that downregulation of Wnt3a expression inhibited cell viability and induced G0/G1 cell cycle arrest via decreased expression of cyclin D1 and c.Myc and increased expression of p21 and p27. In addition, deletion of Wnt3a significantly inhibited migration and invasion by downregulating MMP.2/-7/-9 expression via the MAPK (p38, ERK1/2 and JNK) pathway. In conclusion, our data show that Wnt3a is involved in HCC development. Wnt3a may be an effective target for treatment of HCC.